Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Representative classes of known nucleoside natural product inhibitors of MraY.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: Activity Assay

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Overview of the active site hotspots for MraY inhibition. Top: Surface representation of MraYAA with inhibitor binding site hot spots (HSs) color-coded with the barcode tool (below) as follows: uridine (hot pink), uridine-adjacent (HS1; lime), TM9b/LoopE (HS2; magenta), caprolactam (HS3; pink), hydrophobic (HS4; marine), Mg2+ (HS5; orange), and tunicamycin/sphaerimicin (HS6; deep olive). Bottom: The barcode tool presents a summary of nucleoside inhibitor interactions with different amino acid residues within the uridine pocket and the hotspots (HS) 1–6 in the MraY protein. Each labeled HS residue (MraYAA numbering) represents a distinct site within MraY. Each row pertains to a different compound: carbacaprazamycin (CAR), capuramycin (CAP), 3′-hydroxymureidomycin A (MUR), muraymycin D2 (MD2), tunicamycin (TUN), and sphaerimicin 1 (SPM-1). Dark gray squares indicate the formation of interactions between the inhibitor and residue, while white squares denote the absence of contact. Light gray squares suggest potential interactions where either the amino acid residue side chain or the inhibitor substructure lacks clarity in the crystal structure but likely participates in the binding interaction. Figure recreated from Mashalidis, E. H.; Kaeser, B.; Terasawa, Y.; Katsuyama, A.; Kwon, D.-Y.; Lee, K.; Hong, J.; Ichikawa, S.; Lee, S.-Y. Chemical Logic of MraY Inhibition by Antibacterial Nucleoside Natural Products. Nat. Commun. 2019, 10 (1), 2917. doi: https://doi.org/10.1038/s41467-019-10957-9.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: Inhibition, Binding Assay, Labeling, Residue

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Non-nucleoside small inhibitors of MraY.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques:

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Non-nucleoside inhibitors of MraY derived from nucleoside natural product inhibitors.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: Derivative Assay

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Example of a non-nucleoside inhibitor of MraY, TunR3, derived from tunicamycin natural product.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: Derivative Assay

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Structures of three top-ranking hits and one lower-ranking in silico hits identified as MraYMtb inhibitors from a structure-based virtual screening.37 Figure recreated with permission from Pandey P.; Chatterjee, S.; Berida, T.; et al. Identification of Potential Non-Nucleoside MraY Inhibitors for Tuberculosis Chemotherapy Using Structure-Based Virtual Screening. J. Biomol. Struct. Dyn. 2022, 40 (11), 4832–4849. https://doi.org/10.1080/07391102.2020.1862705.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: In Silico

Journal: Annual reports in medicinal chemistry

Article Title: The challenges and opportunities of developing small molecule inhibitors of MraY

doi: 10.1016/bs.armc.2023.09.005

Figure Lengend Snippet: Sequence alignments of MraY of different lengths across different bacterial species: Aquifex aeolicus strain VF5 (O66465), 359 amino acids; Escherichia coli strain K12 (P0A6W3), 360 amino acids; Staphylococcus aureus strain NCTC 8325/PS 47 (Q2FZ93), 321 amino acids; Borrelia garinii subsp. bavariensis strain ATCC BAA-2496/DSM 23469/PBi (Q661W1), 351 amino acids; Mycobacterium tuberculosis strain ATCC 25618/H37Rv (P9WMW7), 359 amino acid, respectively. The amino acid residues across Gram-negative bacteria (AQUAE, ECOLI, BORGP), Gram-positive (STAA8), and mycobacteria (MYCTU) in dark blue are fully conserved. The less the amino acid residues are conserved, the lighter the blue highlight. The red stars indicate the amino acid residues in the active site of the MraY-bound inhibitors (nucleoside natural products) with reference to MraY Aquifex aeolicus (MraYAA). Uniprot27 and Clustal W in Jalview28 are used for sequence alignment.

Article Snippet: MraY inhibitors from in silico methods A series of non-nucleoside inhibitors of MraY was identified by Gravier-Pelletier’s team using a structure-based virtual screening of a library comprising 500,000 commercially available compounds from Interbioscreen and Otava Chemical Library and their in-house chemical library of 3000 compounds.

Techniques: Sequencing, Bacteria